Leukocyte-endothelial adhesion in the pathogenesis of inflammation
- Amos Etzioni, MD
Amos Etzioni, MD
- Professor of Pediatrics and Immunology
- The Rappaport Faculty of Medicine, Technion, Haifa
Inflammation is a crucial process in the normal defense mechanisms against various pathogens, and leukocytes are the principal cellular mediators of inflammation. Inflammation is characterized histologically by the accumulation of leukocytes in the affected tissue due to migration of circulating leukocytes out of the vasculature, a process which is actively mediated and precisely controlled by leukocytes, the cytokines they produce, and the vascular endothelium . However, excessive or uncontrolled inflammatory responses can lead to the pathologic inflammation seen in many rheumatologic and inflammatory disorders.
Leukocyte trafficking from the blood stream into tissue is important for surveillance of foreign antigens and for rapid leukocyte accumulation at a site of inflammatory response or tissue injury. Although the importance of leukocyte movement towards sites of inflammation was well recognized more than a century ago, the precise molecular mechanisms for leukocyte interactions with the endothelium and the emigration of these cells through the endothelium were elucidated only decades later .
The process of leukocyte-endothelial adhesion during inflammation and the various adhesion molecules involved will be discussed in this topic review. Defects and deficiencies in adhesion molecules are presented separately. (See "Leukocyte-adhesion deficiency".)
Leukocyte-endothelial adhesion involves dynamic interactions between leukocytes and endothelial cells, involving multiple steps. These steps must be precisely orchestrated to ensure a rapid response with only minimal damage to healthy tissue . Interactions between leukocytes and the endothelium are mediated by several families of adhesion molecules, each of which participates in a different phase of the process. The surface expression and activation of these molecules during an inflammatory response is tightly controlled under normal conditions .
Three families of adhesion molecules are of particular importance to the process of leukocyte-endothelial adhesion (table 1):To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Zarbock A, Ley K. Mechanisms and consequences of neutrophil interaction with the endothelium. Am J Pathol 2008; 172:1.
- Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol 2007; 7:678.
- Nourshargh S, Alon R. Leukocyte migration into inflamed tissues. Immunity 2014; 41:694.
- Kansas GS. Selectins and their ligands: current concepts and controversies. Blood 1996; 88:3259.
- McEver RP, Cummings RD. Perspectives series: cell adhesion in vascular biology. Role of PSGL-1 binding to selectins in leukocyte recruitment. J Clin Invest 1997; 100:485.
- Alon R, Rosen S. Rolling on N-linked glycans: a new way to present L-selectin binding sites. Nat Immunol 2007; 8:339.
- Berlin C, Bargatze RF, Campbell JJ, et al. alpha 4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell 1995; 80:413.
- Carlos TM, Harlan JM. Leukocyte-endothelial adhesion molecules. Blood 1994; 84:2068.
- Kelly M, Hwang JM, Kubes P. Modulating leukocyte recruitment in inflammation. J Allergy Clin Immunol 2007; 120:3.
- Luo BH, Carman CV, Springer TA. Structural basis of integrin regulation and signaling. Annu Rev Immunol 2007; 25:619.
- Duncan GS, Andrew DP, Takimoto H, et al. Genetic evidence for functional redundancy of Platelet/Endothelial cell adhesion molecule-1 (PECAM-1): CD31-deficient mice reveal PECAM-1-dependent and PECAM-1-independent functions. J Immunol 1999; 162:3022.
- Wagner DD, Frenette PS. The vessel wall and its interactions. Blood 2008; 111:5271.
- Finger EB, Puri KD, Alon R, et al. Adhesion through L-selectin requires a threshold hydrodynamic shear. Nature 1996; 379:266.
- Lawrence MB, Kansas GS, Kunkel EJ, Ley K. Threshold levels of fluid shear promote leukocyte adhesion through selectins (CD62L,P,E). J Cell Biol 1997; 136:717.
- Kishimoto TK, Rothlein R. Integrins, ICAMs, and selectins: role and regulation of adhesion molecules in neutrophil recruitment to inflammatory sites. Adv Pharmacol 1994; 25:117.
- Smith CW, Rothlein R, Hughes BJ, et al. Recognition of an endothelial determinant for CD 18-dependent human neutrophil adherence and transendothelial migration. J Clin Invest 1988; 82:1746.
- Lawrence MB, Springer TA. Leukocytes roll on a selectin at physiologic flow rates: distinction from and prerequisite for adhesion through integrins. Cell 1991; 65:859.
- Thelen M, Stein JV. How chemokines invite leukocytes to dance. Nat Immunol 2008; 9:953.
- Alon R, Ley K. Cells on the run: shear-regulated integrin activation in leukocyte rolling and arrest on endothelial cells. Curr Opin Cell Biol 2008; 20:525.
- Kinashi T. Intracellular signalling controlling integrin activation in lymphocytes. Nat Rev Immunol 2005; 5:546.
- Wegener KL, Partridge AW, Han J, et al. Structural basis of integrin activation by talin. Cell 2007; 128:171.
- Lefort CT, Ley K. Neutrophil arrest by LFA-1 activation. Front Immunol 2012; 3:157.
- Banno A, Ginsberg MH. Integrin activation. Biochem Soc Trans 2008; 36:229.
- Hidalgo A, Frenette PS. When integrins fail to integrate. Nat Med 2009; 15:249.
- Montanez E, Piwko-Czuchra A, Bauer M, et al. Analysis of integrin functions in peri-implantation embryos, hematopoietic system, and skin. Methods Enzymol 2007; 426:239.
- Muller WA. Leukocyte-endothelial-cell interactions in leukocyte transmigration and the inflammatory response. Trends Immunol 2003; 24:327.
- Alon R, Luscinskas FW. Crawling and INTEGRating apical cues. Nat Immunol 2004; 5:351.
- Nourshargh S, Krombach F, Dejana E. The role of JAM-A and PECAM-1 in modulating leukocyte infiltration in inflamed and ischemic tissues. J Leukoc Biol 2006; 80:714.
- Carman CV, Springer TA. A transmigratory cup in leukocyte diapedesis both through individual vascular endothelial cells and between them. J Cell Biol 2004; 167:377.
- Engelhardt B, Wolburg H. Mini-review: Transendothelial migration of leukocytes: through the front door or around the side of the house? Eur J Immunol 2004; 34:2955.
- Nakagawa M, Bondy GP, Waisman D, et al. The effect of glucocorticoids on the expression of L-selectin on polymorphonuclear leukocyte. Blood 1999; 93:2730.
- Cronstein BN, Molad Y, Reibman J, et al. Colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils. J Clin Invest 1995; 96:994.
- Nuki G. Colchicine: its mechanism of action and efficacy in crystal-induced inflammation. Curr Rheumatol Rep 2008; 10:218.
- Mackay CR. Moving targets: cell migration inhibitors as new anti-inflammatory therapies. Nat Immunol 2008; 9:988.
- Gauvreau GM, Becker AB, Boulet LP, et al. The effects of an anti-CD11a mAb, efalizumab, on allergen-induced airway responses and airway inflammation in subjects with atopic asthma. J Allergy Clin Immunol 2003; 112:331.
- Henderson WR Jr, Chi EY, Albert RK, et al. Blockade of CD49d (alpha4 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model of asthma. J Clin Invest 1997; 100:3083.
- Lebwohl M, Tyring SK, Hamilton TK, et al. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med 2003; 349:2004.
- Gordon KB, Papp KA, Hamilton TK, et al. Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. JAMA 2003; 290:3073.
- Leonardi CL, Papp KA, Gordon KB, et al. Extended efalizumab therapy improves chronic plaque psoriasis: results from a randomized phase III trial. J Am Acad Dermatol 2005; 52:425.
- Picarella D, Hurlbut P, Rottman J, et al. Monoclonal antibodies specific for beta 7 integrin and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) reduce inflammation in the colon of scid mice reconstituted with CD45RBhigh CD4+ T cells. J Immunol 1997; 158:2099.
- Targan SR, Feagan BG, Fedorak RN, et al. Natalizumab for the treatment of active Crohn's disease: results of the ENCORE Trial. Gastroenterology 2007; 132:1672.
- Luster AD, Alon R, von Andrian UH. Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol 2005; 6:1182.
- Stefanelli T, Malesci A, De La Rue SA, Danese S. Anti-adhesion molecule therapies in inflammatory bowel disease: touch and go. Autoimmun Rev 2008; 7:364.
- Polman CH, O'Connor PW, Havrdova E, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354:899.
- Rudick RA, Stuart WH, Calabresi PA, et al. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006; 354:911.
- Yonekawa K, Harlan JM. Targeting leukocyte integrins in human diseases. J Leukoc Biol 2005; 77:129.
- Voulgari PV. Emerging drugs for rheumatoid arthritis. Expert Opin Emerg Drugs 2008; 13:175.
- Genovese MC. Biologic therapies in clinical development for the treatment of rheumatoid arthritis. J Clin Rheumatol 2005; 11:S45.
- The full FDA statement of withdrawl is available online. http://www.fda.gov/medwatch/safety/2009/safety09.htm#Raptiva (Accessed on January 20, 2011).
- Vennegoor A, van Rossum JA, Leurs C, et al. High cumulative JC virus seroconversion rate during long-term use of natalizumab. Eur J Neurol 2016; 23:1079.
- Lobatón T, Vermeire S, Van Assche G, Rutgeerts P. Review article: anti-adhesion therapies for inflammatory bowel disease. Aliment Pharmacol Ther 2014; 39:579.
- McLean LP, Cross RK. Integrin antagonists as potential therapeutic options for the treatment of Crohn's disease. Expert Opin Investig Drugs 2016; 25:263.
- Mitroulis I, Alexaki VI, Kourtzelis I, et al. Leukocyte integrins: role in leukocyte recruitment and as therapeutic targets in inflammatory disease. Pharmacol Ther 2015; 147:123.
- ADHESION MOLECULES
- - Selectin ligands
- - Beta 1 integrins
- - Beta 2 integrins
- Immunoglobulin superfamily molecules
- THE ADHESION CASCADE
- Leukocyte activation and arrest
- - Defects in integrin activation
- Crawling and transmigration
- CLINICAL APPLICATIONS